1. Field of the Invention
The present invention relates to a process for preparing 2,6-dichloropurine. More specifically, the present invention relates to a process for preparing 2,6-dichloropurine, which can be suitably used as a raw material for nucleoside and nucleotide analogues which are useful as pharmaceuticals.
2. Discussion of the Related Art
As a process for preparing 2,6-dichloropurine, there have been known the following processes:
(A) a process comprising chlorinating xanthine with pyrophosphoryl chloride as disclosed in J. Am. Chem. Soc. 78, 3508-10 (1956);
(B) a process comprising chlorinating hypoxanthine or N-oxide of 6-chloropurine with phosphorus oxychloride as disclosed in Japanese Examined Patent Publication Sho 45-11508 and U.S. Pat. No. 3,314,938;
(C) a process comprising four steps using a barbituric acid derivative as a starting material as disclosed in J. Org. Chem. 19, 930(1954) and J. Am. Chem. Soc. 80, 404-8(1958);
(D) a process comprising cyclizing 2,4-dichloro-5,6-diaminopyrimidine as disclosed in U.S. Pat. No. 2,844,576; and the like.
However, there are some defects in process (A) in that the pyrophosphoryl chloride used as a chlorinating agent is complicated to prepare. In process A, pyrophosphoryl chloride is obtained from phosphorous oxychloride via a complicated procedure requiring a high reaction temperature of 165xc2x0 C, a corrosion resistant reaction vessel and a 19-hour reaction time.
In addition, all of the processes (A) to (D) have long preparation steps and require complicated preparation procedures.
An object of the present invention is to provide a process capable of conveniently preparing 2,6-dichloropurine by using an inexpensive starting material.
These and other objects of the present invention will be apparent from the following description.
According to the present invention, there is provided a process for preparing 2,6-dichloropurine comprising the step of chlorinating 2-amino-6-chloropurine with a chlorine source in the presence of a diazotizating agent.
One of the features of the present invention is that the process for preparing 2,6-dichloropurine comprises the step of chlorinating 2-amino-6-chloropurine with a chlorine source in the presence of a diazotizating agent.
2-amino-6-chloropurine is used as a starting material and is readily available, since 2-amino-6-chloropurine has been industrially widely prepared.
The diazotizating agent includes, for instance, alkali metal nitrites, such as sodium nitrite and potassium nitrite; alkyl esters of nitrous acid of which the alkyl moiety has 2 to 6 carbon atoms, such as t-butyl nitrite and isoamyl nitrite; nitrosyl chloride; nitrosylsulfuric acid; nitrogen monoxide; and the like. Among them, sodium nitrite is preferable because it is inexpensive and easily available. In addition, the alkyl esters of nitrous acid are preferable, because they increase the reactivity. The alkali metal nitrite can be dissolved in water before use since the alkali metal nitrite is solid at room temperature.
The amount of the diazotizating agent is 1 to 5 mol, preferably 1 to 2 mol per one mol of 2-amino-6-chloropurine, from the viewpoints of increasing reactivity and economics.
Representative examples of the chlorine source include metal chlorides, chlorinating agents, and the like. These chlorine sources can be used alone or in an admixture including at least two kinds of sources.
The metal chloride includes lithium chloride, potassium chloride, sodium chloride, calcium chloride, magnesium chloride, zinc chloride, nickel chloride, cuprous chloride, cupric chloride, and the like. Among them, lithium chloride is preferable from the viewpoints of increasing reactivity and improving yield.
The chlorinating agent includes chlorine, hydrochloric acid, thionyl chloride, alkyl chlorides such as methyl chloride, N-chlorosuccinimide, and the like. Among them, hydrochloric acid is preferable from the viewpoints of cost and improving yield. The concentration of hydrochloric acid is preferably not less than 10%.
It is preferable that the chlorine source is a combination of the metal chloride and the chlorinating agent, from the viewpoints of increasing reactivity and improving yield.
Among the combinations of the metal chloride and the chlorinating agent, it is preferable that the metal chloride is lithium chloride and the chlorinating agent is chlorine, N-chlorosuccimide or thionyl chloride, from the viewpoints of increasing reactivity, improving yield and suppressing the generation of by-products. It is more preferable that the metal chloride is lithium chloride and the chlorinating agent is chlorine.
When the metal chloride is used as the chlorine source, an acid can be added to the metal chloride. The acid includes acetic acid, propionic acid, formic acid, phosphoric acid and the like. Among them, acetic acid is preferable, from the viewpoints of increasing reactivity and suppressing the generation of by-products. As to the combination of the metal chloride and the acid, it is preferable that the metal chloride is lithium chloride and the acid is acetic acid, from the viewpoints of increasing reactivity, improving yield and suppressing the generation of by-products.
When the chlorine source is composed of the metal chloride alone or the chlorinating agent alone, it is desired that the amount of the chlorine source is 1 to 50 mol, preferably 5 to 20 mol per one mol of 2-amino-6-chloropurine, from the viewpoint of increasing reactivity, suppressing the generation of by-products and increasing economic advantages.
When the combination of the metal chloride and the chlorinating agent is used as the chlorine source, the ratio of the metal chloride to the chlorinating agent (molar ratio of the metal chloride/the chlorinating agent), is preferably 1/1 to 10/1, more preferably 2/1 to 6/1. In this case, it is desired that the amount of the chlorine source is 1 to 10 mol, preferably 3 to 6 mol per one mol of 2-amino-6-chloropurine.
In the present invention, first 2-amino-6-chloropurine can be suspended or dissolved in a solvent.
The solvent includes, for instance, water, organic solvents such as N,N-dimethylformamide and N,N-dimethylacetamide, and the like. The amount of the solvent is not limited to that which is specified, and can be altered by proper adjustment. In the case where hydrochloric acid or the combination of the metal chloride and the acid is used as the chlorine source, a solvent is not used, since the acid acts as a solvent. Therefore, when the acid is employed, 2-amino-6-chloropurine can be suspended in the acid.
Also, an alkali metal hydroxide, ammonia or the like can be added to the solvent in order to increase the solubility of 2-amino-6-chloropurine, and thereby 2-amino-6-chloropurine can be partly or completely dissolved.
2-Amino-6-chloropurine can be chlorinated by properly mixing the suspension or solution of 2-amino-6-chloropurine with the chlorine source and a diazotizating agent.
The reaction temperature during the chlorination depends upon the kinds of the chlorine source and the diazotizating agent. It is desired that the reaction temperature is xe2x88x9220xc2x0 to 100xc2x0 C., preferably xe2x88x9210xc2x0 to 60xc2x0 C., from the viewpoints of increasing reactivity and suppressing formation of the by-products.
The reaction time depends upon the reaction conditions and the like. The reaction time is usually from 1 to several hours.
The resulting reaction solution can be subjected to an after-treatment in an ordinary method to collect the resulting 2,6-dichloropurine.
The 2,6-dichloropurine can be collected by, for instance, a method comprising neutralizing the reaction solution with a base such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium carbonate or its aqueous solution to cause precipitation, and collecting precipitated crystals by filtration; or a method comprising extracting 2,6-dichloropurine with acetonitrile or ethyl acetate.
After the extraction, the formed 2,6-dichloropurine can be collected as crystals by concentrating the extract. Thereafter, 2,6-dichloropurine can be purified by an ordinary method.
Thus, a desired compound 2,6-dichloropurine can be conveniently prepared from an inexpensive compound as a starting material.